Current oncological therapy utilises mostly eradicative methods such as surgery and actinotherapy, striving to eradicate or at least reduce the primary tumour. An accompanying assumption is that the remaining latent tumour population will be eradicated by natural immunological surveillance of the organism itself. This basic therapeutic approach is modified by adjutant and lately also nonadjuvant chemotherapy. The utilised therapeutic combination represents thus a compromise between the positive therapeutical and negative immunosuppressive effect of all the a.m. methods and individual cancerogenic effect of actinotherapy and chemotherapy. For complexities sake should be mentioned also therapy with hormones, which methodically represents a class of chemotherapy including the a.m. negative, i.e., immunosuppressive and cancerogenic effects. The resulting positive effect of such combined therapy is thus based on a significant immune tolerance of the organism both towards the existing disease and therapy as such. Such a situation is neither the rule nor happens often. Subsequent or simultaneous therapeutical efforts leading to immunomodulation through immunotherapy thus are logically doomed to failure due to the extent of disease and the extend of tissue catabolism. As part of the contest for valid oncological therapy, there is currently a renaissance of enzymotherapy, a method essentially rooted in the first case of this century (Beard, Chadto et Windus, London 1911). Their successors were Freund and Kaminer (Freund E., Kaminer G., Springerverlag, Wien 1925, Freund E., Med.Wschr., 12, 1934) and Christiani (Christiani A., Krebsforsch., 1938, 47, 176). Theoretical and experimental findings of these authors were then followed by clinical studies of Wolf and Benitez, Wolf and Ransberger (Wolf M., Ransberger K., Enzymtherapie, Maudrich. Wien 1970). These authors showed the selective oncolytic effect of animal and plant hydrolases (proteases) and participation of various enzymes in potentiation of the oncolytic effect. These authors also observed enteral resorption of hydrolases and glycosidases (amylases) and laid the foundations for peroral therapy including the WOBE MUGOS (trademark of Mucos Pharma GmbH, Geretsried, Germany) combinations of enzymes (e.g., papain, trypsin and calf thymus) for therapeutical use.
Systemic enzymotherapy is based on clinical utilisation of experimental data about effects of active proteases. These are systemic antiinflammatory effects and effects on fibrinolysis, stimulation of cytokine production (TNF-alpha, IL 2,6), stimulation of polymorphonuclear leukocyte production and of the macrophage system. Concerning local antitumour effects there appears among others a selective oncolytic effect leading to diminishing the efficacy of tumour cell membrane adhesive molecules and together with systemic fibrinolytic activity also prevention of metastase formation. There should be also mentioned the paper of Yoneda et al. (Yoneda et al., Cancer Res., 1994 54, 2509), who, after application of a partially purified extract of pork pancretic cells to mice with a human spinocellular skin tumour observed a beneficial effect on anorexia, weight loss, development of cachexia and survival times. The authors partially purified the pancreatic factor without defining its effective substance.
When using active proteases for therapy one has to take into account some facts, which limit the effect of such therapy. These are:
a) Pancreatic proteases in the blood stream and interstitium are rapidly inactivated by present polyvalent inhibitors (alpha-1 protease inhibitor, antithrombin III, C1-inhibitor and chymotrypsin inhibitor). Possible disruption of the alpha 2-macroglobulin protease complex in the presence of a substrate with high affinity for the protease was proven for many proteolytical systems (e.g., alpha 2--macroglobulin (MG)--plasmin-fibrin), but for the system alpha 2--macroglobulin (MG)--trypsin-trypsin receptor remains still only a theoretical consideration. An advantage of the inhibitor-protease bond is a decrease in antigenicity of the foreign protease due to complex formation. PA1 b) Trypsin-like proteases in a similar way to other proteases (i.e. lysosomal cathepsin B) can increase the degree of invasivity of tumour cells through destruction of surrounding host tissue (Koivanen E., Int. J. Cancer 1991, 47 (4), 592)). PA1 c) Trypsin can influence the blood protease system, which is internally related by activation and inhibition mechanisms (trypsin influences detrimentally the coagulation--fibrinolytic system, and directly leads to formation of kinins, mediators of inflammation and pain, from plasmatic kininogens, etc.) PA1 a) protease proenzymes PA1 b) amylase PA1 trypsinogen PA1 chymotrypsinogen PA1 proelastase and PA1 prekallikrein